Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Cancer Sci. 2018 Dec;109(12):4015-4024. doi: 10.1111/cas.13815. Epub 2018 Oct 31.
Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.
胃癌是日本和全球癌症死亡的第三大主要原因。尽管先前的研究确定了与胃癌相关的各种遗传变异，但宿主遗传因素在很大程度上尚未确定。为了在日本人群中鉴定新的胃癌基因座，在此，我们使用 6171 例病例和 27178 例对照进行了大规模全基因组关联研究，并随后进行了三项复制分析。使用总共 11507 例病例和 38904 例对照的分析在 12q24.11-12 上鉴定出两个新的基因座(rs6490061，P=3.20×10 ，优势比[OR]为 0.905)和 20q11.21(rs2376549，P=8.11×10 ，OR 为 1.109)。rs6490061 位于 CUX2 基因的内含子 19 中，其表达受幽门螺杆菌感染抑制。rs2376549 包含编码抗菌肽的 DEFB 家族基因簇内。我们还发现 9q34.2 上 ABO 基因座的 rs7849280 存在显著关联(P=2.64×10 ，OR 为 1.148)。胃黏膜组织中的 CUX2 和 ABO 表达与 rs6490061 和 rs7849280 显著相关(P=0.0153 和 8.00×10 )。我们的研究结果表明遗传变异在胃癌发病机制中的重要作用。
